Orthogonally Functionalized Nanoscale Micelles for Active Targeted Codelivery of Methotrexate and Mitomycin C with Synergistic Anticancer Effect

• Published in: Molecular pharmaceutics Vol. 12; no. 3; pp. 769 - 782
• Main Authors: Li, Yang, Lin, Jinyan, Wu, Hongjie, Chang, Ying, Yuan, Conghui, Liu, Cheng, Wang, Shuang, Hou, Zhenqing, Dai, Lizong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.03.2015
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Biopharmaceutics; Drug Carriers - chemistry; Drug Delivery Systems; Drug Synergism; Female; HeLa Cells; Humans; Methotrexate - administration & dosage; Methotrexate - pharmacokinetics; Mice; Mice, Inbred BALB C; Mice, Nude; Micelles; Mitomycin - administration & dosage; Mitomycin - pharmacokinetics; Nanocapsules - chemistry; Nanotechnology; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; Rats; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays; targeted drug delivery; methotrexate; mitomycin C; micelles; combination cancer chemotherapy
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp5006068

The design of nanoscale drug delivery systems for the targeted codelivery of multiple therapeutic drugs still remains a formidable challenge (ACS Nano, 2013, 7, 9558–9570; ACS Nano, 2013, 7, 9518–9525). In this article, both mitomycin C (MMC) and methotrexate (MTX) loaded DSPE-PEG micelles (MTX–M–MMC) were prepared by self-assembly using the dialysis technique, in which MMC–soybean phosphatidylcholine complex (drug–phospholipid complex) was encapsulated within MTX-functionalized DSPE-PEG micelles. MTX–M–MMC could coordinate an early phase active targeting effect with a late-phase synergistic anticancer effect and enable a multiple-responsive controlled release of both drugs (MMC was released in a pH-dependent pattern, while MTX was released in a protease-dependent pattern). Furthermore, MTX–M–MMC could codeliver both drugs to significantly enhance the cellular uptake, intracellular delivery, cytotoxicity, and apoptosis in vitro and improve the tumor accumulation and penetration and anticancer effect in vivo compared with either both free drugs treatment or individual free drug treatment. To our knowledge, this work provided the first example of the systemically administrated, orthogonally functionalized, and self-assisted nanoscale micelles for targeted combination cancer chemotherapy. The highly convergent therapeutic strategy opened the door to more simplified, efficient, and flexible nanoscale drug delivery systems.